Inhibition of platelet activation, aggregation and/or adhesion by hypothermia

ABSTRACT

A method for treating acute coronary syndromes (i.e., unstable angina or non-Q-wave MI) or transient ischemic attacks in a human or animal patient by placing a heat exchange apparatus in the patient&#39;s vasculature and using that heat exchange apparatus to cool the patient to a temperature (e.g. 30-36° C.) at which platelet inhibition (i.e., inhibition of platelet activation and/or aggregation and/or adhesion) occurs. Anti-shivering drugs or anesthesia may be administered to patients whose body temperature is cooled below that patient&#39;s shivering threshold (typically approximately 35.5 C). If it is determined that platelet inhibition is no longer desirable, such as when the patient is about to undergo a surgical or interventional procedure wherein bleeding could be problematic, the hypothermia-induced platelet inhibition may be rapidly reversed by using the intravascular heat exchange apparatus to re-warm the patient&#39;s body to normothermia or near normothermia.

RELATED APPLICATIONS

This application is a continuation of copending U.S. patent applicationSer. No. 10/408,617 filed Apr. 7, 2003, which is a continuation of U.S.patent application Ser. No. 09/790,249 filed Feb. 21, 2001 now issued asU.S. Patent No. 6,544,282, the entire disclosures of which are expresslyincorporated herein by reference.

FIELD OF THE INVENTION

This invention relates generally to methods for medical treatment andmore particularly to the intravascular application of hypothermia totreat acute coronary syndromes or other disorders that are treatable byinhibiting platelet activation and/or platelet aggregation and/orplatelet adhesion.

BACKGROUND OF THE INVENTION

As used in this patent application the terms “anti-platelet” and“platelet inhibiting” shall mean any inhibition of platelet activationand/or platelet aggregation and/or platelet adhesion.

Platelet activation, aggregation and/or adhesion are believed to playsignificant rolls in the pathogenesis of many vaso-occlusive disorderssuch as unstable angina, acute myocardial infarction, reocclusion ofvessels following balloon angioplasty, transient ischemic attacks andstrokes. Generally speaking, when a blood vessel becomes damaged,chemical agonists bind with certain binding sites on circulatingplatelets, causing the platelets to become activated. The types of bloodvessel wall damage that can trigger platelet activation includeperforation or injury to the vessel wall, progression of atheroscleroticplaque, the performance of some interventional procedure (e.g.,angioplasty, atherectomy or stenting) which stretches the vessel wall orcauses intimal tearing, or other causes. When activated, plateletsinteract with fibrinogen, fibronectin and other clotting factors causingthem to adhere to the affected blood vessel wall and to aggregate withone another and with other blood cells (e.g., leukocytes). Thisactivation, adherence and aggregation of platelets leads to theformation of a thrombus or blood clot.

Platelet inhibiting drug therapy (i.e., therapy that prevents or detersplatelet activation and/or aggregation and/or adhesion) has been used ina wide variety of cardiovascular disease states. Some plateletinhibiting drugs, such as aspirin and ticlopidine (Ticlid™ RocheLaboratories, Inc., Nutley, N.J.) prevent platelet activation byinhibiting the agonists which cause the platelets to activate. However,each of these agonist-inhibiting drugs is largely specific to only oneplatelet activation pathway. For example, aspirin is believed toactively block platelet activation that occurs via a cyclooxygenasepathway but has little or no efficacy in blocking platelet activationthat occurs via adenosine diphosphate (ADP). On the other hand,ticlopidine is effective in inhibiting platelet aggregation that occursvia ADP but has little or no efficacy in inhibiting platelet activationthat occurs through the cyclooxygenase pathway. Other antiplateletdrugs, known as glycoprotein IIb/IIIa inhibitors, are thought to inhibitthe activation of platelets by preventing binding sites located on theplatelet membrane glycoprotein complex IIb/IIIa (GP IIb/IIIa) frombecoming active even after the platelet has been triggered by anactivation agonist. In this manner, the GP IIb/IIIa binding sites arerendered unavailable for binding with fibrinogen, fibronectin and otherclotting factors, and as a result platelet aggregation, plateletadhesion or clot formation are inhibited. Examples of GP IIb/IIIainhibitors include abciximab (ReoPro™, Centocor, Inc., Malvern, Pa.),eptifibatide (Integrilin™, COR Therapeutics, South San Francisco,Calif.) and tirofiban (Aggrast™, Merck & Co., West Point, Pa.).

One drawback associated with the use of antiplatelet drug therapy isthat it can be expensive, especially when the newer glycoproteinIIb/IIIa inhibiting drugs are used. Also, as with virtually all drugs,the antplatelet drugs can cause side effects. Moreover, onceantiplatelet drugs have been administered, the duration of theirantiplatelet action can last for as long as four to six weeks. Theresultant ongoing platelet inhibiting effect can be problematic in somecases, such as where some hemorrhage occurs or where a decision is madeto subject the patient to surgery or some other invasive procedure,during or after which control of bleeding may be highly desirable. Inthis regard, as explained in the following paragraphs, the inability torapidly reverse the effect of antiplatelet drugs can be particularlyproblematic in patients who suffer from certain acute cardiovascularrequire immediate treatment for acute coronary syndromes, such asunstable angina or non-Q wave myocardial infarction (MI), but who maysubsequently be required to undergo cardiac surgery or another invasiveprocedure wherein control of bleeding is desirable.

Accute Coronary Syndromes: Unstable Angina and Non-Q Wave MI

Unstable angina, also referred to as “accelerating angina”, “new-onsetangina” or “progressive angina” is often characterized by a) chest painthat persists even in the absence of exercise, b) an increase in theseverity, frequency, or duration of anginal chest pain, and/or c) theonset of anginal pain a lower levels of exercise than before. It hasbeen reported that unstable angina occurs at some time in the lives ofapproximately 6 out of 10,000 people. Unstable angina typically arisesin patient's who have a history of stable or exercise induced angina dueto the presence of atherosclerotic plaque in one or more of thepatient's coronary arteries. Non-Q-wave MI is a condition in which ablockage within a coronary artery causes a mild MI. A more serious MIoften follows the occurrence of a non-q wave MI. In fact, patients whosuffer from a non-Q wave MI are considered to be at even higher risk fordeath than individuals with unstable angina.

Both unstable angina and non-Q wave MI fall into a category of serious,life-threatening emergency conditions known as acute coronary syndromes.Both the onset of unstable angina and the occurrence of non-Q wave MIcan be attributed to the rupture of a coronary atherosclerotic plaque.The rupture of the coronary atherosclerotic plaque in turn causesplatelets to aggregate and blood clots to form, thereby converting theprior relatively stable narrowing of the coronary artery into anunstable (“high-grade”) occlusion that severely limits blood flow to aregion of the heart muscle, even when the patient is at rest.

Patients with acute coronary syndromes, such as unstable angina andnon-Q wave MI, run a high risk of a fatal or non-fatal heart attack.These acute coronary syndromes require immediate hospitalization and theprompt administration of initial stabilizing treatment is a criticalfirst step in preventing a possibly fatal heart attack from occurring.The goals of such initial stabilizing treatment is to reduce theseverity of the acute symptoms and to prevent the situation fromevolving into a full blown MI or potentially fatal cardiac arrhythmia.The immediate treatment often includes the administration of drugs thatprevent or deter platelet aggregation or blood clotting, such asaspirin, heparin, or platelet inhibiting drugs as discussed in moredetail herebelow as well as other agents such as nitroglycerin (often bypaste or intravenously) beta-blockers, calcium channel blockers,antianxiety medications, and medications to control blood pressure andabnormal heart rhythms.

After the drug therapy has been initiated, the patient may be observedto determine if the condition will stabilize as a result of theaggressive medical management. If the patient does not stabilize, thepatient will typically be evaluated to determine if CABG (coronaryartery bypass grafting) surgery, PTCA (percutaneous transluminalcoronary angioplasty) or some other surgical or interventional procedureis indicated. If surgery or an interventional procedure is indicated andthe patient is otherwise a candidate for such surgery or intervention,the patient may then be taken to the catheterization lab for a PTCA orto the operating room for a CABG. In these patients the presence ofpreviously administered platelet inhibiting drugs (i.e., drugs thatinhibit platelet activation and/or aggregation and/or adhesion) can be aproblem.

Transient Ischemic Attacks:

Another condition that may result from platelet activation, aggregationand/or adhesion is known as a transient ischemic attack (TIA). A TIAtypically lasts from a few minutes to a few hours. TIA's are caused byinterrupted blood flow to a part of the brain, resulting in neurologicsymptoms such as slurred speech, dizziness, double vision, or weaknessin a limb. The occurrence of a TIA indicates that the patient is at asignificant risk of undergoing a full-blown ischemic stroke, potentiallyresulting in permanent brain damage or death. The rapid induction ofplatelet inhibition during or after the occurrence of a TIA may help tominimize the risk that the patient will suffer a full scale embolicstroke. However, after more definitive diagnostic tests are performed itmay be determined that the patient is a candidate for an interventionalor surgical procedure designed to alleviate blockages in the carotid orcerebral vasculature or that the cause of the patient's symptoms is not,in fact, a TIA but rather a small localized area of bleeding in thepatient's brain. In such instances, it would be highly desirable to beable to cease or reverse any platelet inhibition therapy that has begun,but such cessation or reversal of the platelet inhibition may take aslong as weeks (e.g., 4-6 weeks).

Thus, in view of the foregoing, there exists a need for the developmentof a platelet inhibiting treatment that may be rapidly administered to apatient who has suffered an acute coronary syndrome (unstable angina ornon-Q wave MI) or a TIA, but which can be rapidly discontinued orreversed if it is no longer indicated, such as when the patient isselected to undergo an invasive interventional or surgical procedure(e.g., PTCA or CABG) where a risk of untoward bleeding is identified.

SUMMARY OF THE INVENTION

The present invention provides a method for treating an acute coronarysyndrome (i.e., unstable angina or non-Q-wave MI) or TIA or otherwisecausing platelet inhibition (i.e., prevention or deterrence of plateletactivation and/or platelet aggregation and/or platelet adhesion) in ahuman or veterinary patient. In general, the method comprises the stepsof a) diagnosing the acute coronary syndrome or other disorder whereinplatelet inhibition is a desirable therapeutic objective, b) placing aheat exchange apparatus in heat exchange proximity with the patient'sblood and c) using the heat exchange apparatus to cool the patient'sblood to a temperature at which the desired platelet inhibition occurs.The heat exchange apparatus may be, for example a heat exchange catheterwith a heat exchange region placed in the vasculature of the patient sothat it directly exchanges heat with the blood flowing over the heatexchange region. Alternatively it may be a heat exchange catheter havinga heat exchange region placed in the esophagus of a patient and exchangeheat with blood in the aorta through the esophageal and aortic walls. Itmay even be an enhanced method of cooling blood through the skin of thepatient, provided that whatever heat exchange method is used is fast andefficient enough to effect a reduction of blood and tissue temperaturesufficient to inhibit platelet activation sufficient for thethearapeutic use here described.

In humans, blood flowing in heat exchange proximity to the heat exchangeapparatus may be cooled to a temperature of less than 36° C. andtypically in the range of 32° C. to 36° C. The temperature of the bloodand/or the target tissue will be reduced to therapeutically sufficientlevels fairly fast, generally in less than 3 hours, and withintravascular hypothermia applied for the purpose of treating an acutecoronary syndrome, typically less than 15 minutes after the catheter isplaced and begins cooling. The patient's blood may be maintained at thecooled temperature for any period of time desired, but typically suchtreatment will be maintained for a period of time from approximately 1hour to approximately 3 days. Specifically, for patients being treatedfor unstable angina, the hypothermic treatment will typically bemaintained for approximately 1 to 6 hours.

Further in accordance with the invention, the foregoing method ofcausing platelet inhibition may be performed in patient's who aresuffering from unstable angina, non-Q wave MI and/or TIA's. Thehypothermia-induced platelet inhibition caused by this method may bemaintained until the patient either a) spontaneously stabilizes so as tocause platelet inhibition to be no longer indicated, b) becomesstabilized by medical therapy which may or may not include plateletinhibiting drugs and/or c) undergoes an interventional (e.g., PTCA,atherectomy, etc.) or surgical (CABG) procedure that obviates the needfor continued platelet inhibition.

Further in accordance with the invention, the foregoing method ofcausing platelet inhibition by hypothermia may be performed as analternative or stand-alone treatment or may be combined with otherplatelet inhibiting therapies or drugs, such as aspirin; non-steroidalantiinflamatories; ticlopidine; anticoagulants (e.g., heparin orwarfarin); GP IIb/IIIa inhibitors (e.g., abcixmab or tirofiban) or anypossible combination thereof. The hypothermic platelet inhibitingtreatment of the present invention, when used in combination withplatelet inhibiting drugs, may allow for a desirable reduction in thedosage(s) of the platelet inhibiting drugs used, thereby avoidingdrug-related side effects or facilitation faster clearance andtermination of the effect(s) of such drug(s) after cessation of drugtreatment.

Further aspects and particulars of the present invention will becomeapparent to those of skill in the art upon reading and understanding ofthe detailed description and examples set forth herebelow.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective drawing of an embodiment of the catheter of theinvention.

FIG. 1A is a perspective drawing of an alternative tie-down at theproximal end of the catheter shown in FIG. 1.

FIG. 2 is a cross-sectional drawing of the shaft of the catheter takenalong the line 2-2 in FIG. 1.

FIG. 3 is a cross-sectional drawing of the heat exchange region of thecatheter taken along the line 3-3 in FIG. 1.

FIG. 3A is a cross-sectional view through line 3A-3A of FIG. 1.

FIG. 4 is a perspective drawing of a segment of the heat exchange regionof the catheter within the circle 4-4 in FIG. 1.

FIG. 5 is a cross-sectional drawing of the heat exchange region of thecatheter taken along the line 5-5 in FIG. 1.

FIG. 6 is a perspective drawing of a segment of the heat exchange regionof the catheter within the circle 6-6 in FIG. 1.

FIG. 7 is a perspective drawing of the multi-lobed balloon of oneembodiment of the invention.

FIG. 8 is a perspective drawing of the distal portion of the shaft ofone embodiment of the invention.

FIG. 9 is a perspective drawing, partially in ghost, of the heatexchange region formed by the shaft and multi-lobed balloon of FIGS. 7and 8.

FIG. 10 is an expanded view of the attachment of the central lumen ofthe balloon to the shaft of the catheter of FIG. 9 showing the regionwithin the circle 10-10 in FIG. 9.

FIG. 10 A is an expanded view of the plug between the shaft and thecentral lumen of the balloon of the catheter of FIG. 9 showing theregion within the circle 10A-10A in FIG. 9.

FIG. 11 is a perspective view of a portion of a multi-lobed, curvilinearheat exchange balloon that forms a portion of one embodiment of theinvention.

FIG. 11A is a cross sectional view of the heat exchange region takenalong the line 11A-11A in FIG. 11.

FIG. 12 is a sectional view of the proximal portion of the heat exchangeregion of one embodiment of the invention.

FIG. 12A is a cross-sectional view of a portion of the heat exchangeregion taken along the line 12A-12A of FIG. 12.

FIG. 12B is a cross-sectional view of a portion of the heat exchangeregion taken along the line 12B-12B of FIG. 12.

FIG. 12C is a cross-sectional view of a portion of the heat exchangeregion taken along the line 12C-12C of FIG. 12.

FIG. 13 is a sectional view of the distal portion of the heat exchangeregion of one embodiment of the invention.

FIG. 13A is a cross-sectional view of a portion of the heat exchangeregion taken through line 13A-13A of FIG. 13.

FIG. 13B is a cross-sectional view of a portion of the heat exchangeregion taken through line 13B-13B FIG. 13.

FIG. 14 is a general flow diagram of a platelet inhibition method of thepresent invention

FIG. 15 is a flow diagram of a method for treating an acute coronarysyndrome (e.g., unstable angina or non-Q wave MI) or TIA in accordancewith the present invention.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

The following detailed description is provided for the purpose ofdescribing only selected embodiments or examples of the invention and isnot intended to describe all possible embodiments and examples of theinvention.

A. General Method for Hypothermic Platelet Inhibition

FIG. 14 is a flow diagram which generally shows the manner in which themethod of the present invention may be used in humans to cause plateletinhibition after an initial diagnosis or clinical impression of unstableangina, non-Q-wave MI, transient ischemic attack (TIA) or other disorderwherein platelet inhibition is desired, has been reached. As used hereinthe term platelet inhibition means any or all of; a) prevention ordeterrence of platelet activation, b) prevention or deterrence ofplatelet adhesion and/or c) prevention or deterrence of off plateletaggregation. As shown in FIG. 14, after the initial diagnosis orclinical impression has been reached, the next step of the generalmethod is to position a heat exchange apparatus in heat exchangingproximity with the blood of the human or veterinary patient. This stepmay be accomplished as described above, with any effective method havingadequate speed and efficiency but is preferably effected bypercutaneously inserting and transluminally advancing a heat exchangecatheter, heat exchange probe or other or elongate heat exchangingmember into a blood vessel, for example the inferior vena cava (IVC).Typically the heat exchanging member will be a flexible catheter whichhas a heat exchanger or heat exchange region located at or near itsdistal end. However, it will be appreciated that various other elongate,percutaneously insertable, transluminally advanceable heat exchangeapparatus may be employed. In general, examples of heat exchangecatheters and related devices & controllers that are useable in thisstep of the method are described in PCT International Application No.PCT/US99/18939 and U.S. Pat. No. 5,486,208 (Ginsburg), U.S. Pat. No.5,149,676 (Ginsburg), U.S. Pat. No. 6,149,673 (Ginsburg), U.S. Pat. No.5,174,285 (Fontenot), U.S. Pat. No. 5,344,436 (Fontenot, et al.), U.S.Pat. No. 5,957,963(Dobakl I I), U.S. Pat. No. 6,096,608(Dobak I I, etal.) and U.S. Pat. No. 6,126,684(Gobin, et al.), the entire disclosuresof which expressly incorporated herein by reference. In particular, onepresently preferred intravascular heat exchange catheter system for usein the present invention is described in U.S. Provisional ApplicationNo. 60/181,249 the entirety of which is expressly incorporated herein byreference and portions of which are set forth in the paragraphsherebelow.

With further reference to FIG. 14, the second general step of the methodmay be to use a heat exchange apparatus that had been positioned in thepatient's vasculature to cool the patient's blood to a temperature atwhich platelet inhibition (i.e., inhibition of platelet activationand/or aggregation and/or adhesion) occurs. It has previously beenestablished that hypothermia can inhibit platelet activation andaggregation. see, Michelson, A. D., et al., Reversible Inhibition ofHuman Platelet Activation by Hypothermia In Vivo and In Vitro, ThrombHaemost 71 (5): 633-40 (1994) However, hypothermia-induced plateletinhibition is not known to have been previously used as a means fortreating acute coronary syndromes (unstable angina or non Q-wave MI) orTIAs. Nor has it been known to use an intravascular heat exchangeapparatus to effect hypothermia for the purpose of inhibiting plateletactivation, aggregation or adhesion.

Furthermore, as shown in FIG. 14, purposeful and relatively rapidreversal of the hypothermia-induced platelet inhibition may beaccomplished by re-warming the patient. This re-warming of the patientmay be carried out using the same intravascular heat exchange catheteras was used to previously cool the patient. It is not believed to havebeen heretofore known to use re-warming of a patent to reverse plateletinhibition for a therapeutic purpose, especially when such re-warming isperformed using the same heat exchange device and particularly the sameintravascular heat exchange device as had previously been used to coolthat patient.

The use of the intravascular heat exchange apparatus in the presentinvention generally permits hypothermia to be induced more rapidly andwith substantially greater control than by noninvasive means such aswrapping the patient in a hypothermia blanket. The temperature to whichthe patient is cooled to effect the desired platelet inhibition istypically below about 36° C., and preferably in the range ofapproximately 32 to 36° C. In this invention, either whole-bodyhypothermia or partial-body hypothermia may be used. When whole-bodyhypothermia is used, the patient's core body temperature may bemonitored and maintained at the desired platelet inhibition temperature.When partial-body hypothermia is used the temperature of a desiredorgan, limb or anatomical portion of the body will be monitored andmaintained at the desired platelet inhibition temperature. Concurrentlywith the hypothermia, the patient may be anesthetized or may receivemedications or other therapy to prevent or lessen shivering ordiscomfort due to the hypothermia. Examples of medications that may beadministered to minimize shivering or discomfort during the hypothermictreatment are described in PCT International Application No.PCT/US00/20321. The specific drugs used to prevent shivering may includemeperidine, buspirome, dexmedetomidine and/or combinations thereof. Inthe alternative, where it is undesirable to administer anti-shiveringdrugs, the patient's body temperature may be maintained blownormothermia (to achieve some platelet inhibition) but above theshivering threshold, which is typically about 35-35.5° C.

In accordance with the invention hypothermia may be administered as thesole platelet inhibition treatment, at least for a period of timesufficient to allow physicians to fully evaluate the patient's conditionand to reach an appropriate decision regarding the initiation ofplatelet inhibiting drug therapy. In other instances, it may bedesirable to administer intravascular hypothermia in accordance withthis invention concurrently with the administration of plateletinhibiting drugs or other platelet inhibiting therapies so as to speedthe onset of the desired platelet inhibiting effect, to reduce thedosages of platelet inhibiting drugs or other platelet inhibitingtherapies required, or to otherwise improve the efficacy or reduce thetoxicity of the platelet inhibiting treatment being used.

The application of hypothermia in accordance with this invention may, inaddition to effecting direct platelet inhibition, simultaneously reduceoverall tissue damage to an affected region. For example it may reduceblood vessel wall inflammation or microvascular injury thought to serveas a focal point for adhesion of platelets or thrombus formation. Thisantiinflamatory or vessel-wall-protecting effect that accompanies theanti-platelet effect of intravascular hypothermia may not be realizedwith anti-platelet drug therapy alone. Further, the application ofhypothermia may, simultaneously with reduction of platelet inhibition,protect the target tissue in other ways. For example, hypothermia hasbeen found to be generally myoprotective (i.e., protective of musclecells against damage from insults like hypothermia or ischemia) and ifintravascular hypothermia is applied to the blood in the IVC immediatelybefore the blood enters the heart, it might simultaneously provideprotection against damage by platelet activation and provide protectionagainst damaging chemical cascades such as repurfusion damage to cellmembranes. Likewise, hypothermia has been shown to be generallyneuroportective, and if anti-platelet hypothermia is applied as atreatment for TIA's, the hypothermia might simultaneously protect thebrain tissue against damage by excitatory amino acids, destructive freeradicals and the like in addition to the protection for the directdamage done by activated platelets.

B. A Preferred Intravascular Heat Exchange Catheter System

Referring to FIGS. 1 through 10A, in one embodiment, the catheter iscomprised of a shaft 50 with a heat exchange region 100 thereon. Theshaft has two roughly parallel lumens running through the proximalshaft, an inflow lumen 52 and an outflow lumen 54. The shaft generallyalso comprises a working lumen 56 running therethrough for the insertionof a guide wire, or the application of drugs, radiographic dye, or thelike to the distal end of the catheter. The heat exchange regioncomprises a four-lumen balloon, with three outer lumens 58, 60, 62disposed around an inner lumen 64 in a helical pattern. In theparticular embodiment shown, the balloon preferably makes one fullrotation about the inner lumen 64 for each 2 to 4 inches of length. Allfour lumens 58, 60, 62 and 64 are thin walled balloons and each outerlumen 58, 60, 62 shares a common thin wall segment 66, 68, 70 with theinner lumen. The balloon is approximately twenty-five centimeters long,and when inflated has an outer circumference 72 of approximately 0.328in. When deflated, the profile is generally about 9 French (3 French is1 mm in diameter). When the balloon portion is installed on the shaft,both the proximal end 74 of the balloon and the dital end 76 of theballoon are sealed around the shaft in fluid tight seals, as describedmore fully herebelow. Heat exchange fluid may be directed in through theinflow lumen, return through the outer lobes of the balloon in heatexchange proximity with blood flowing over the outside of the balloon,and then out through the outflow lumens, as will be described in greaterdetail below.

The catheter is attached at its proximal end to a hub 78. At the hub,the guide wire lumen 56 communicates with a guide wire port 80, theinflow lumen 52 is in fluid communication with an inflow port 82, andthe outflow lumen 54 is in communication with an outflow port 84.Attached at the hub and surrounding the proximal shaft is a length ofstrain relief tubing 86 which may be, for example, a length of heatshrink tubing. The strain relief tubing may be provided with suturetie-downs 88, 90. Alternatively, a butterfly tie-down 92 may beprovided. (See FIG. 1A).

Between the strain relief tubing 86 and the proximal end of the balloon74, the shaft 50 is extruded with an outer diameter of about 0.118inches. The internal configuration is as shown in cross-section in FIG.2. Immediately proximal of the balloon attachment 74, the shaft isnecked down 94. The outer diameter of the shaft is reduced to about0.100 to 0.110 inches, but the internal configuration with the threelumens is maintained. Compare, for example, the shaft cross-section ofFIG. 2 with the cross-section of the shaft shown in FIG. 3. This lengthof reduced diameter shaft remains at approximately constant diameter ofabout 0.100 to 0.110 inches between the necked down location at 94 and adistal location 96 where the outflow lumen is sealed and the guide wireextension tube 98 is attached as will be described.

At the necked down location 94, a proximal balloon marker band 102 isattached around the shaft. The marker band is a radiopaque material suchas a platinum or gold band or radiopaque paint, and is useful forlocating the proximal end of the balloon by means of fluoroscopy whilethe catheter is within the body of the patient.

At the location marked by the marker band, all four lobes of the balloonare reduced down and fastened around the inner member 67 in afluid-tight seal. This may be accomplished by folding the outer lobes ofthe balloon 58, 60, 62 down around the inner lumen 64, placing a sleeve,for example a short length of tubing, snuggly over the folded-down outerlumens of the balloon and inserting adhesive, for example by wicking theadhesive, around the entire inner circumference of the sleeve. The innerlumen is then fastened to the shaft using a second short length oftubing. The second short length for example 1 mm, of intermediate tubing104 is heat welded to the inside of the inner lumen. The intermediatetube has an outer diameter approximately the same as the inner diameterof the inner lumen. The intermediate tube is then slid over the shaft atabout the location of the neck-down region near the proximal marker 102,and adhesive 106 is wicked into the space between the inside of theintermediate tubing and the outer surface of the shaft 50. A similarprocess may be used to attach the distal end of the balloon, as will bedescribed, except that the distal end of the balloon is attached downaround the guide wire extension tube 98 rather than the shaft.

Just distal of the proximal balloon seal, under the balloon within theinner lumen, an elongated window 108 is cut through the wall of theoutflow lumen in the shaft. Along the proximal portion of the balloonabove this window, five slits, e.g. 110, are cut into the common wallbetween each of the outer lumens 58, 60, 62 and the inner lumen 64.Because the outer lumens are twined about the inner lumen in a helicalfashion, each of the outer tubes passes over the outflow lumen of theinner shaft member at a slightly different location along the length ofthe inner shaft and, therefore, an elongated window 108 is cut into theoutflow lumen of the shaft so that each outer lumen has at least oneslit e.g. 110 that is located over the window in the shaft.Additionally, there is sufficient clearance between the outer surface ofthe shaft and the wall of the inner lumen to allow relativelyunrestricted flow of heat exchange fluid through all 5 slits in eachouter lumen, around the shaft, and through the elongate window 108 intothe outflow lumen 54 in the shaft 50.

Distal of the elongated window in the outflow lumen, the inner lumen 64of the four-lumen balloon is sealed around the shaft in a fluid tightplug. Referring to FIG. 10 a, the plug is formed by, for exampleshrinking a relatively thick length of PET tubing to form a length ofplug tubing 112 where the inner diameter of the length of plug tubing isapproximately the same as the outer diameter of the shaft at thelocation where the plug is to be formed. The plug tubing is slid overthe shaft and fits snugly against the shaft. The shaft is generallyformed of a material that is not heat shrinkable. As may be seen in FIG.10A and FIG. 3, some clearance exists between the outer wall of theshaft and the inner wall of the inner lumen 64. The walls of the innerlumen are composed of thin heat shrinkable material, for example PET. Aprobe with a resistance heater on the distal end of the probe isinserted into the guide wire lumen of the shaft and located with theheater under the plug tubing. The probe is heated, causing the heatshrink wall of the inner lumen to shrink down against the plug tubing,and the plug tubing to shrink slightly down against the shaft. Theresultant mechanical fit is sufficiently fluid tight to prevent theoutflow lumen and the space between the shaft and the wall of the innerlumen from being in fluid communication directly with the inner memberor the inflow lumen distal of the plug except through the outer lumensas will be detailed below.

Just distal of the plug, the outflow lumen is closed by means of a heatseal 99, and the inflow lumen is skived to form an opening 101 to theinner member. This may be accomplished by necking down the shaft at 96,attaching a guide wire extension tube 98 to the guide wire lumen, andsimultaneously opening the inflow lumen 101 to the interior of the innerlumen and heat sealing the outflow lumen shut 101. The guide wireextension tube continues through the inner lumen, beyond the distal sealof the balloon (described below) to the distal end of the catheter 114and thereby creates communication between the guide wire port 80 and thevessel distal of the catheter for using a guide wire to place thecatheter or for infusing drugs, radiographic dye, or the like beyond thedistal end of the catheter.

The distal end of the balloon 76 is sealed around the guide wireextension tube in essentially the same manner as the proximal end 74 issealed down around the shaft. Just proximal of the distal seal, fiveslits 116 are cut into the common wall between each of the three outerlumens 58, 60 62 of the balloon and the inner lumen 64 so that each ofthe outer lumens is in fluid communication with the inner lumen.

Just distal of the balloon, near the distal seal, a distal marker band118 is placed around the guide wire extension tube. A flexible length oftube 120 may be joined onto the distal end of the guide wire tube toprovide a soft tip to the catheter as a whole.

In use, the catheter is inserted into the body of a patient so that theballoon is within a blood vessel, for example in the inferior vena cava(IVC). Heat exchange fluid is circulated into the inflow port 82,travels down the inflow lumen 52 and into the inner lumen 64 distal ofthe plug tube 112. The heat exchange fluid fills the inner lumen andtravels down the inner lumen, thence through slits 116 between the innerlumen 64 and the three outer lumens 58, 60, 62.

The heat exchange fluid then travels back through the three outer lumensof the balloon to the proximal end of the balloon. Since outer lumensare wound in a helical pattern around the inner lumen, at some pointalong the length of the balloon near the proximal end and proximal ofthe plug, each outer lumen is located over the portion of the shafthaving the window to the outflow lumen 108. There is also sufficientclearance between the wall of the inner lumen and the shaft, asillustrated in FIG. 3, that even the slits that are not directly overthe window 108 allow fluid to flow into the space between the wall ofthe inner lumen and the outer wall of the shaft 50 and then through thewindow 108 and into the outflow lumen. The heat exchange fluid thenflows down the outflow lumen and out the outflow port 84. At a fluidpressure of 41 pounds per square inch, flow of as much as 500milliliters per minute may be achieved with this design.

Counter-current circulation between the blood and the heat exchangefluid is highly desirable for efficient heat exchange between the bloodand the heat exchange fluid. Thus if the balloon is positioned in avessel where the blood flow is in the direction from proximal toward thedistal end of the catheter, for example if it were placed from thefemoral vein into the Inferior Vena Cava (IVC) cava, it is desirable tohave the heat exchange fluid in the outer balloon lumens flowing in thedirection from the distal end toward the proximal end of the catheter.This is the arrangement described above. It is to be readilyappreciated, however, that if the balloon were placed so that the bloodwas flowing along the catheter in the direction from distal to proximal,for example if the catheter was placed into the IVC from a jugularinsertion, it would be desirable to have the heat exchange fluidcirculate in the outer balloon lumens from the proximal end to thedistal end. Although in the construction shown this is not optimal andwould result is somewhat less effective circulation; this could beaccomplished by reversing which port is used for inflow direction andwhich for outflow.

Where heat exchange fluid is circulated through the balloon that iscolder than the blood in the vessel into which the balloon is located,heat will be exchanged between the blood and the heat exchange fluidthrough the outer walls of the outer lumens, so that heat is absorbedfrom the blood. If the temperature difference between the blood and theheat exchange fluid (sometimes called “ΔT”), for example if the blood ofthe patient is about 37° C. and the temperature of the heat exchangefluid is about 0° C., and if the walls of the outer lumens conductsufficient heat, for example if they are of very thin (0.002 inches orless) plastic material such as polyethylene terephthalate (PET), enoughheat may be exchanged (for example about 200 watts) to lower the bloodtemperature sufficiently to effect hypothermic anti-platelet activity,and to cool the temperature downstream of the catheter, for example ofthe heart, sufficiently for therapeutic inhibition of plateletactivation, aggregation and/or adhesion. If the cooling catheter is leftin place long enough for example for over half an hour, the entire bodytemperature of the patient may be cooled sufficiently for hypothermicanti-platelet activity. In this way, for example, blood to the brain andeven the brain tissue itself may be cooled sufficiently for therapeutichypothermic anti-platelet effect.

The helical structure of the outer lumens has the advantage overstraight lumens of providing greater length of heat exchange fluid pathfor each length of the heat exchange region. This creates additionalheat exchange surface between the blood and the heat exchange fluid fora given length of balloon. It may also provide for enhanced flowpatterns for heat exchange between flowing liquids. The fact that theheat exchange region is in the form of an inflatable balloon also allowsfor a minimal insertion profile, for example 9 French or less, while theheat exchange region may be inflated once inside the vessel for maximumdiameter of the heat exchange region in operation.

Automated control of the process is optional. Examples of apparatus andtechniques that may be used for automated control of the process aredescribed in U.S. Pat. Nos. 6,149,676 and 6,149,676 and co-pending U.S.patent application Ser. No. 09/138,830, the entireties of which areexpressly incorporated herein by reference.

Referring now to FIGS. 11 through 13B, in another example of a preferredembodiment, the heat exchange region is in the form of a series of fivelumens arranged side-by-side in a configuration that may be looselydescribed as a twisted ribbon. The heat transfer fluid circulates to andfrom the heat exchange region 202 via channels formed in the shaft 206in much the same manner as previously described for shaft 50. Indeed,although not depicted, the shaft has a similar internal configuration asthe shaft previously described with an inflow lumen, an outflow lumen,and a working lumen. Although also not depicted, a hub is attached atthe proximal end of the shaft which is maintained outside the body; thehub has a guide wire port communicating with the working lumen, aninflow port communicating with the inflow lumen, and an outflow portcommunicating with the outflow lumen. Heat exchange fluid is directedinto the catheter through the inflow port and removed from the catheterthrough the outflow port. A guide wire, or alternatively medicaments,radiographic fluid or the like are introduced through the guide wireport and may thus be directed to the distal end of the catheter.

FIGS. 11 and 11A illustrate this embodiment of a heat exchange region202 comprising a plurality of tubular members that are stacked in ahelical plane. More specifically, a central tube 220 defines a centrallumen 222 therewithin. A pair of smaller intermediate tubes 224 a, 224 battaches to the exterior of the central tube 220 at diametricallyopposed locations. Each of the smaller tubes 224 a, 224 b defines afluid lumen 226 a, 226 b therewithin. A pair of outer tubes 228 a, 228 battaches to the exterior of the intermediate tubes 224 a, 224 b inalignment with the aligned axes of the central tube 220 and intermediatetubes 224 a, 224 b. Each of the outer tubes 228 a, 228 b defines a fluidlumen 230 a, 230 b within. By twisting the intermediate and outer tubes224 a, 224 b, 228 a, 228 b around the central tube 220, the helicalribbon-like configuration of FIG. 11 is formed.

Now with reference to FIGS. 12 and 12A-12C, a proximal manifold of theheat exchange region 202 will be described. The shaft 206 extends ashort distance, desirably about 3 cm, within the central tube 220 and isthermally or adhesively sealed to the interior wall of the central tubeas seen at 250. As seen in FIG. 12A, the shaft 206 includes a planarbulkhead or web 252 that generally evenly divides the interior space ofthe shaft 206 into an inflow lumen 254 and an outflow lumen 256. Aworking or guide wire lumen 260 is defined within a guide wire tube 262that is located on one side of the shaft 206 in line with the bulkhead252. Desirably, the shaft 206 is formed by extrusion. The outflow lumen256 is sealed by a plug 264 or other seal at the terminal end of theshaft 206. The inflow lumen 254 remains open to the central lumen 222 ofheat exchange region 202. The guide wire tube 262 continues a shortdistance and is heat bonded at 270 to a guide wire extension tube 272generally centered within the central tube 220.

A fluid circulation path is illustrated by arrows in FIG. 12 andgenerally comprises fluid passing distally through the inflow lumen 254and then through the entirety of the central lumen 222. The heatexchange fluid is directed from the central lumen 222 to theintermediate and outer tubes as will be described below, and returnsthrough the lumens 226 a, 226 b, and 230 a, 230 b of the intermediateand outer tubes 224 a, 224 b, and 228 a, 228 b, respectively, and entersreservoirs 274 and 275. Alternatively, two windows may be formed 276 anda counterpart not shown in FIG. 12 one helical twist farther down theshaft, between each side of the twisted ribbon (i.e., lumens 224 a and224 b on one side, and 228 a and 228 b on the other side). In this way,one reservoir from each side of the twisted ribbon is formed in fluidcommunication with the outflow lumen 256 (configuration not shown).Fluid then enters the outflow lumen 256 through apertures, e.g., 276,provided in the central tube 220 and a longitudinal port 278 formed inthe wall of the shaft.

A distal manifold of the heat exchange region 202 is shown and describedwith respect to FIGS. 13 and 13A-13B. The outer tubes 228 a, 228 b taperdown to meet and seal against the central tube 220 which, in turn,tapers down and seals against the guide wire extension tube 272. Fluidflowing distally through the central lumen 222 passes radially outwardthrough a plurality of apertures 280 provided in the central tube 220.The apertures 280 open to a distal reservoir 282 in fluid communicationwith lumens 226 a, 226 b, and a distal reservoir 281 in fluidcommunication with lumens 230 a, 230 b of the intermediate and outertubes 224 a, 224 b, and 228 a, 228 b.

With this construction, heat exchange fluid introduced into the inputport 240 will circulates through the inflow lumen 254, into the centrallumen 222, out through the apertures 280, and into the distal reservoir282. From there, the heat exchange fluid will travel proximally throughboth intermediate lumens 226 a, 226 b and outer lumens 230 a, 230 b tothe proximal reservoirs 274 and 275. Fluid then passes radially inwardlythrough the apertures 276 and port 278 into the outflow lumen 256. Thenthe fluid circulates back down the shaft 206 and out the outlet port242.

The ribbon configuration of FIGS. 11-13B is advantageous for severalreasons. First, the relatively flat ribbon does not take up asignificant cross-sectional area of a vessel into which it is inserted.The twisted configuration further prevents blockage of flow through thevessel when the heat exchange region 202 is in place. The helicalconfiguration of the tubes 224 a, 224 b, 228 a, 228 b also aids tocenter the heat exchange region 202 within a vessel by preventing theheat exchange region from lying flat against the wall of the vesselalong any significant length of the vessel. This maximizes heat exchangebetween the lumens and the blood flowing next to the tubes. Because ofthese features, the twisted ribbon configuration is ideal for maximumheat exchange and blood flow in a relatively small vessel such as thecarotid artery. As seen in FIG. 11A, an exemplary cross-section has amaximum diameter of about 5 mm, permitting treatment of relatively smallvessels. The helical pattern of the balloon in the fluid flow may act toinduce a gentle mixing action of the flowing blood to enhance heatexchange between the heat exchange surface and the blood withoutinducing hemolytic damage that would result from more violent churningaction.

The deflated profile of the heat exchange region is small enough to makean advantageous insertion profile, as small as 7 French for someapplications. Even with this low insertion profile, the heat exchangeregion is efficient enough to adequately exchange heat with bloodflowing past the heat exchange region to alter the temperature of theblood sufficient for anti-platelet action and affect the temperature oftissue downstream of the heat exchange region. Because of its smallerprofile, it is possible to affect the temperature of blood in smallervessels and thereby provide treatment to more localized body areas.

This configuration has a further advantage when the heat exchange regionis placed in a tubular conduit such as a blood vessel, especially wherethe diameter of the vessel is approximately that of the major axis(width) of the cross section of the heat exchange region. Theconfiguration tends to cause the heat exchange region to center itselfin the middle of the vessel. This creates two roughly semicircular flowchannels within the vessel, with the blood flow channels divided by therelatively flat ribbon configuration of the heat exchange region. It hasbeen found that the means for providing maximum surface for heatexchange while creating minimum restriction to flow is thisconfiguration, a relatively flat heat exchange surface that retains twoapproximately equal semi-circular cross-sections. This can be seen inreference to FIG. 11A if the functional diameter of the dashed circle300 is essentially the same as the luminal diameter of a vessel intowhich the twisted ribbon is placed. Two roughly semi-circular flow paths302, 304 are defined by the relatively flat ribbon configuration of theheat exchange region, i.e. the width or major axis (from the outer edgeof 228 a to the outer edge of 228 b) is at least two times longer thanthe height, or minor axis (in this example, the diameter of the innertube 222) of the overall configuration of the heat exchange region. Ithas been found that if the heat exchange region occupies no more thanabout 50% of the overall cross-sectional area of the circular conduit, ahighly advantageous arrangement of heat exchange to flow is created. Thesemi-circular configuration of the cross-section of the flow channels isadvantageous in that, relative to a round cross-sectioned heat exchangeregion (as would result from, for example, a sausage shaped heatexchange region) the flow channels created minimize the surface to fluidinterface in a way that minimizes the creation of laminar flow andmaximizes mixing. Maximum blood flow is important for two reasons. Thefirst is that flow downstream to the tissue is important, especially ifthere is obstruction in the blood flow to the tissue. The second reasonis that heat exchange is highly dependent on the rate of blood flow pastthe heat exchange region, with the maximum heat exchange occurring withmaximum blood flow, so maximum blood flow is important to maximizingheat transfer.

C. A Preferred Method for Hypothermic Treatment of Acute CoronarySyndromes:

FIG. 14 is a flow chart that generally depicts the use of hypothermia totreat unstable angina, non-Q wave MI or TIA's by application ofanti-platelet hypothermia. Once the diagnosis is made, a heat exchangeapparatus is placed in heat exchange proximity with the patient's blood.In many cases, that will be the placement of an intravascular catheterhaving a heat exchange region placed in the IVC, but may be any othermeans that is fast and effective enough to accomplish anti-platelethypothermia. For example, if a surface cooling apparatus is placed inheat exchange proximity to the patient's blood in the patient's skin,that may suffice to exchange sufficient heat with the blood butgenerally only if the normal thermoregulatory defenses such asvasoconstriction are defeated so that effective heat transfer couldoccur, and the body's normal thermoregulatory defense of generating heatthrough shivering is sufficiently disabled that the adequate cooltemperature can be reached.

Once a hypothermic state capable of causing the desired anti-plateleteffect (i.e., inhibition of platelet activation and/or aggregationand/or adhesion) is reached, it may be maintained by continued heatexchange with the patient's blood at the precise amount to maintain adesired temperature. This may be accomplished by means of sensing thepatient's core temperature and removing more heat if the temperaturebegins to rise, or removing less heat if the temperature begins to fallbelow the desired level. Means of accomplishing this temperaturemaintanence with an intravascular heat exchange catheter are set out inU.S. Pat. Nos. 6,149,676 and 6,149,676, both to Ginsburg which areincorporated herein in full, and also in PCT International ApplicationNo. PCT/US99/18939 to Ginsburg et al, previously incorporated.

When it is desired to restore the patient to normal platelet activity,the platelet inhibition may be reversed, either by allowing the patientto become normothermic or optionally by rewarming the blood, perhapswith the same heat exchange apparatus that was used to induce theanti-platelet hypothermia.

FIG. 15 shows a flow diagram of a more specific, presently preferredmethod for using intravascular hypothermia to induce platelet inhibition(as defined herein) in a human patient who suffers from some conditionwherein platelet inhibition is desired such as an acute coronarysyndrome such as unstable angina or non-Q wave MI.

Typically, the patient will be assessed in a hospital emergency room orphysician's office and an initial diagnosis or clinical impression ofunstable angina or non-Q wave MI will be made. Promptly after thediagnosis or clinical impression of unstable or non-Q wave MI has beenreached, an intravascular heat exchange catheter, a such as (forexample) the catheter 100 shown in FIG. 1, will be percutaneouslyinserted into a vein such as the femoral vein and advanced through thevenous vasculature until the heat exchange region of the catheter 100becomes positioned within the patient's thorax in the inferior venacava, superior vena cava or right atrium. A chest x-ray or otherappropriate imaging study may be performed to verify the properpositioning of the catheter 100 and it will be appreciated thatradio-opaque markers or other imageable markers may be formed all on ornear the catheter's heat exchange region to facilitate verification thatthe heat exchange region has been properly positioned. Thereafter, theheat exchange region of the catheter 100 will be cooled, for example bycirculating cold heat exchange fluid through the interior of the heatexchange balloon Such circulation of cooled heat exchange fluid throughthe heat exchanger will cause venous blood which flows through the venacava or right atrium to become cooled as it passes in heat exchangeproximity to the heat exchange region of the catheter 100.Temperature-measuring probes may be positioned on or in the patient'sbody (e.g., in the patient's esophagus, on the tympanic membrane, in theaxillary region, in the rectum, in the patient's blood stream at alocation that is not within heat exchange proximity to the heat exchangeregion of the catheter 100 etc) to monitor the patient's core bodytemperature. Circulation of cooled heat exchange fluid through the heatexchange region of the catheter will preferably continue until thepatient's core body temperature reaches a target temperature at whichthe desired platelet inhibition will occur. In this example, the patientis unanesthetized and has not been treated with antishivering drugs and,thus, a target temperature of approximately 35.5-36.5° C. will bemaintained. By maintaining the patient's temperature above approximately35.5° C. severe shivering will most likely be avoided. It is to beappreciated, however, that the shivering threshold may vary from patientto patient or from time point to time point and, thus, it may bedesirable to adjust the patient's core temperature, as needed, to avoidsevere shivering or discomfort. Alternatively, the patient may beanesthetized or medicated with anti-shivering medications as describedherein. While the patient is maintained in a hypothermic state, thepatient's condition will be observed, cardiac enzymes may be monitoredand appropriate diagnostic studies may be performed to determine theseverity of the acute coronary syndrome or TIA that is ongoing. In atleast some cases, especially those where the patient is being treatedfor an acute coronary syndrome, angiography studies or otherpre-operative/pre-intervention assessments (e.g., imaging studies,diagnostic tests) may be performed while the patient is maintained inthe hypothermic state. These assessment may then be used to determinewhether the patient is a candidate for a catheter-based intervention(e.g., PTCA, stenting, atherectomy, thrombectomy) or cardiac surgicalintervention (e.g., CABG). Thereafter, a decision may be made to sendthe patent to the catheterization laboratory or radiology suite for acatheter-based intervention, to the operating room for a surgicalintervention. Alternatively, a decision may be made not to perform acatheter-based intervention or surgery and, instead, to begin drugtreatment long term medical management of the patient's condition. Inany event, should a stroke or heart attack occur, the already presenthypothermia may present some protection for the neural tissues andcardiac muscle tissue. Some patients in whom an acute cardiac syndromesare initially diagnosed will become stabilized spontaneously or withappropriate ongoing medical therapy (e.g., the ongoing oral or topicaladministration of anti-rhythmic agents, beta-blockers, anticoagulantsand/or platelet inhibiting drugs). If the patient become stabilizedspontaneously or via medical therapy, the patient may then be re-warmedto a normothermic temperature (i.e., approximately 37° C. for most humanpatients) and the heat exchange catheter may be removed. Prior to orduring the rewarming, appropriate antiplatelet drug therapy may becommenced and will be continued if a decision has been made to maintainthe patient on ongoing oral drug therapy after the patient leaves thehospital. In patients who do not become stabilized spontaneously or byemergency medical therapy, it may be appropriate for the patient toundergo an interventional procedure (e.g., PTCA, stenting oratherectomy) or it may be appropriate for the patient to undergo acardiac surgical procedure (e.g., open or thoracoscopic CABG).Catheter-based interventional procedures like PTCA, stenting oratherectomy are typically performed in unanesthetized patients and, inthose cases, it may be appropriate to continue the intravascularhypothermic treatment of the present invention during the performance ofthe catheter-based interventional procedure. Thereafter, if theinterventional procedure has been successfully accomplished and theacute coronary syndrome is obviated, the intravascular hypothermictreatment may be discontinued and the heat exchange catheter removed. Inpatients who have received intravascular hypothermia as the soleplatelet inhibiting treatment, the cessation of the hypothermia willalso terminate the platelet inhibition and, therefore, post-procedurebleeding from the vascular access site at which the catheter(s) wereinserted will not be complicated by ongoing platelet inhibition as mayhave occurred if non-reversible platelet inhibiting drugs had beenadministered prior to the interventional procedure.

In unstable angina patients that undergo cardiac surgical interventionsuch as CABG sometimes have hypothermia during surgery as the standardof care, often induced and maintained by a blood heat exchanger in thecardiopulmonary by pass machine. In such cases, hypothermic plateletinhibition may be administered to the patient prior to the patient goingon the by-pass machine, and reversed by warming after the patient hasbeen removed from the bypass machine.

In cardiac procedures where the patient is not placed on acardiopulmonary by pass machine, hypothermic therapy has generally notbeen available. In such cases, however, the method of the presentinvention may be employed to provide platelet inhibition byadministration of hypothermia, and subsequent reversal by re-warming byuse of an intravascular heat exchange catheter as described above.

Although several illustrative examples of means for practicing theinvention are described above, these examples are by no means exhaustiveof all possible means for practicing the invention. The scope of theinvention should therefore be determined with reference to the appendedclaims, along with the full range of equivalents to which those clamsare entitled.

1. A method for lessening the potential for secondary thrombo-embolicevents in a patient suffering from non-Q wave myocardial infarction,unstable angina or a transient ischemic attack, said method comprisingthe steps of: a) reaching a diagnosis or clinical impression that thepatient is suffering from non-Q wave myocardial infarction, unstableangina or transient ischemic attack; b) placing an intravascular heatexchange apparatus within the venous vasculature of the patient; c)using the intravascular heat exchange apparatus to cool the patient'sbody to a core temperature within the range of 32 degrees C. to 36degrees C., resulting in systemic hypothermia-induced plateletinhibition without concomitant administration to the patient ofanticoagulant or platelet inhibiting drugs; d) administering treatmentfor the non-Q wave myocardial infarction, unstable angina or transientischemic attack; e) determining that the patient is no longer sufferingfrom the non-Q wave myocardial infarction, unstable angina or transientischemic attack; and, thereafter, f) reversing the platelet inhibitionby re-warming the patient to a temperature at which platelet inhibitionno longer occurs.
 2. A method according to claim 1 wherein Step bcomprises: inserting a heat exchange catheter having a heat exchangeregion into venous vasculature of a patient; and placing said heatexchange catheter so that the heat exchange region is in contact withblood flowing to the heart; and wherein Step c comprises: exchangingheat with the blood at the heat exchange region for a period of timesufficient to cause said platelet inhibition.
 3. A method as in claim 1wherein the intravascular heat exchange apparatus is used to maintain atleast a portion of the patient's body at a temperature at which plateletinhibition occurs for less than 4 hours.
 4. A method according to claim1 wherein the temperature is between approximately 32 C andapproximately 34 C.
 5. A method according to claim 1 wherein theintravascular heat exchange apparatus is an elongate flexible catheterthat comprises a heat exchanger.
 6. A method according to claim 5wherein the heat exchanger of the catheter comprises less than the fulllength of the catheter that becomes inserted in the patient'svasculature.
 7. A method according to claim 1 wherein the heat exchangeapparatus is placed in the patient's vena cava.
 8. A method according toclaim 7 wherein the heat exchange apparatus is placed in the patient'sinferior vena cava.
 9. A method according to claim 7 wherein the heatexchange apparatus is placed in the patient's superior vena cava.
 10. Amethod according to claim 1 wherein the intravascular heat exchangeapparatus has a heat exchange surface whereon at least one projection isformed to increase an effective heat exchange surface area.
 11. A methodaccording to claim 10 wherein the at least one surface projectioncomprises a fin.
 12. A method according to claim 11 wherein said fincomprises a raised area on at least a blood-contacting surface of theheat exchanger.
 13. A method according to claim 11 wherein said fincomprises a ridge.
 14. A method according to claim 11 wherein said fincomprises a bulge.
 15. A method according to claim 1 wherein theintravascular heat exchange apparatus comprises a heat exchanger throughwhich heat exchange fluid is circulated.
 16. A method according to claim15 wherein said heat exchanger comprises a heat exchange balloon.
 17. Amethod according to claim 16 wherein the balloon is a single-lobedballoon.
 18. A method according to claim 16 wherein the balloon is amulti-lobed balloon.
 19. A method according to claim 1 wherein theintravascular heat exchange apparatus comprises a heat exchanger that ismetallic.
 20. A method according to claim 1 wherein at least Step c iscarried out concurrently with treatment of the patient by plateletinhibiting drugs.
 21. A method according to claim 1 wherein at leastStep c is carried out concurrently with the presence within thepatient's body of a platelet-inhibiting amount of at least one drugselected from the group consisting of: aspirin; non-steroidalantiinflamatories; ticlopidine; anticoagulants; heparin; warfarin; GPIIb/IIIa inhibitors; abcixmab; tirofiban; and, possible combinationsthereof.
 22. A method according to claim 21 wherein the plateletinhibiting effect of the drug is enhanced by the concurrent applicationof intravascular hypothermia.
 23. A method according to claim 1 whereinthe intravascular heat exchange apparatus is placed in contact withblood that reached the heart soon after exchanging heat with the heatexchange apparatus so that the temperature of the heart is selectivelyaltered.
 24. A method according to claim 1 wherein the patient isunanesthetized and has not been medicated to deter shivering and whereinStep c is carried out until the patient's core body temperature islowered to a temperature at which platelet inhibition occurs but isabove the temperature at which substantial shivering occurs.
 25. Amethod according to claim 1 wherein the intravascular heat exchangeapparatus is a balloon catheter wherein a heat exchange region is aballoon having a balloon with an interior space and an exterior surface,said exterior sufrace in heat exchange proximity with the blood flowingpast said heat exchange region when said balloon catheter is placed incontact with blood flowing to the heart, said balloon catheter having ashaft, said shaft having an inflow lumen and an outflow lumen, saidinflow lumen in fluid communication with the interior space of saidballoon, said outflow lumen in fluid communication with said interiorspace of said balloon, and including the additional step of circulatingheat exchange fluid in said inflow lumen and out said outflow lumen. 26.A method according to claim 1 comprising the additional step of sensingthe temperature of the patient, and adjusting the step of exchangingheat with the blood in response to the temperature sensed.
 27. A methodaccording to claim 26 wherein the temperature sensed is the temperatureof the patient's blood at a location that is not within heat exchangeproximity to the intravascular heat exchange apparatus.
 28. A methodaccording to claim 26 wherein the temperature sensed is the patient'sbody temperature as measured at the patient's tympanic membrane.
 29. Amethod according to claim 26 wherein the temperature sensed is thepatient's rectal temperature.
 30. A method according to claim 26 whereinthe temperature sensed is representative of the whole body temperatureof the patient.
 31. A method according to claim 26 comprising theadditional steps of selecting a target temperature, maintaining thepatient at said target temperature when said temperature is reached. 32.A method according to claim 31 comprising the additional steps of addingheat when the sensed temperature is below the target temperature, andremoving heat from the blood when the sensed temperature is above thetarget temperature.
 33. A method according to claim 1 further comprisingthe step of: after reversing the platelet inhibition by re-warming thepatient to a temperature at which platelet inhibition no longer occurs,treating the patient with a treatment that would result in increasedrisk of bleeding complications if the platelet inhibition had not beenreversed.
 34. A method according to claim 33 wherein the treatmentperformed in step d comprises forming an incision or puncture in thepatient's body.
 35. A method according to claim 34 wherein the treatmentcomprises surgery.
 36. A method according to claim 35 wherein thesurgery comprises heart surgery.